Nuclear magnetic resonance, hereinafter NMR, is relatively a recent method in radiology with respect to the study and imaging of intact biological systems. Like X-rays and ultrasound procedures, NMR is a non-invasive analytical technique employed as a means to examine a body. Unlike X-rays, however, NMR is a non-ionizing, non-destructive process that can be employed continuously to a host. Further, NMR imaging is capable of providing anatomical information comparable to that supplied by X-ray "CAT" scans. In comparison to ultrasound, the quality of projections (images) reconstructed from currently known NMR techniques either rival or transcend those observed with ultrasound procedures. Thus, these rather unusual and highly desirable characteristics provide NMR with present potential to be one of the most versatile and useful diagnostic tools ever used in biological and medical communities.
Basically, NMR is a process that results when nuclei with magnetic moments are subjected to a magnetic field. If electromagnetic radiation in the radio-frequency of the spectrum is subsequently applied, the magnetized nuclei will emit a detectable signal having a frequency similar to the one applied.
More specifically, NMR predicates on the fact that nuclei with an odd number of nucleons have an intrinsic magnetism resulting from an angular momentum, or spin, of such nuclei. Resembling a bar magnet, the spin property generates a magnetic dipole, or magnetic moment, around such nuclei. Thus, when two external fields are applied to an object, the strong magnetic field causes the dipoles for such nuclei, e.g., nuclei with spin designated 1/2, to align either parallel or anti-parallel with said magnetic field. Of the two orientations, the parallel alignment requires the nuclei to store less energy and hence is the stable or preferred orientation. As to the second applied field, comprising radio-frequency waves carrying a precise frequency or quantum of electromagnetic radiation, it will cause such nuclei to nutate or flip into the less stable orientation. In an attempt to re-establish the preferred parallel or stable orientation, the excited nuclei will emit the absorbed electromagnetic radio waves at a frequency characteristic to the nuclei being detected.
Thus, the NMR technique detects radio-frequency signals emitted from nuclei with an odd number of nucleons as a result of a process undergone by such nuclei when exposed to at least two externally applied fields. If a third magnetic field in the form of a gradient is applied, nuclei with the same magnetogyric constant will nutate at different frequencies, i.e., Larmor frequencies, depending upon the location within the object. Thus, similar nuclei in an object can be detected discriminately for a particular region in said object according to their Larmor frequency corresponding to a particular magnetic field strength along the applied magnetic gradient, as demonstrated by the following equation f.sub.o =(.gamma.)H.sub.o wherein f.sub.o is the Larmor frequency, .gamma. is the magnetogyric constant, and H.sub.o is the applied magnetic field.
Unfortunately, there are several factors that may limit the usefulness of NMR applications in vivo. In general, NMR is an insensitive radiologic modality requiring significant amounts of nuclei with magnetic moments, i.e., an odd number of nucleons, to be present in an object. Consequently, not all nuclei in vivo are present in sufficient quantities to be detected by present NMR techniques. Further, not all nuclei in vivo have magnetic moments, i.e., an odd number of nucleons. Some of the more common isotopes that do not have magnetic moments which are found in vivo include carbon-12, oxygen-16, and sulfur-32. Thus, current NMR applications in vivo are restricted to those nuclei that have magnetic moments and are sufficiently abundant to overcome the insensitivity of present NMR techniques.
Heretofore, NMR applications in vivo have almost invariably been concerned with imaging or detecting the water distribution within a region of interest derived from the detection of proton resonance. Other nuclei not only have lower intrinsic NMR sensitivities, but also are less abundant in biological material. Consideration has, however, been given to the use of other nuclei such as phosphorous-31 which represents the next best choice for NMR in vivo applications due to its natural and abundant occurrence in biological fluids. For example, phosphorous-31 NMR has been found to provide a useful means for determining indirectly intracellular pH and Mg.sup.++ concentration simply by measuring the chemical shift of the inorganic phosphate resonance in vivo and determining from a standard titration curve the pH or Mg.sup.++ concentration to which the chemical shift corresponds. The type of information available from NMR. IN: Gadian, D. G.: Nuclear Magnetic Resonance and Its Applications to Living Systems. First Edition. Oxford: Clarendon Press. pp. 23-42 (1982); Moon, R. B. and Richards, J. H.: Determination of Intracellular pH By .sup.31 P Magnetic Resonance. J. Biological Chemistry. 218(20):7276-7278 (Oct. 25, 1973). In addition, sodium-23 has been used to image an isolated perfused heart with a medium containing 145 mM sodium in vivo. Unfortunately, difficulties with these nuclei arise because of the inherent sensitivity losses due to the lower resonant frequencies of these nuclei. Moon, R. B. and Richards, J. H.: Determination of Intracellular pH By .sup.31 P Magnetic Resonance. J. Biological Chemistry. 218(20):7276-7278 (Oct. 25, 1973).
Another stable element which is uniquely suited for NMR imaging is fluorine because its intrinsic sensitivity practically is commensurate with that of protons, it has a spin of 1/2, so as to give relatively uncomplicated, well-resolved spectra, its natural isotopic abundance is 100 percent, it gives large chemical shifts, and because its magnetogyric constant is similar to that of protons, the same equipment can be used. Unfortunately, fluorine NMR applications in vivo are in effect not conducted due to the practical non-existence of fluorine in biological materials. However, nuclear medicine procedures using the positron emitter fluorine-18 are well documented and include, for example, bone scanning, brain metabolism and infarc investigations using fluorodeoxyglucose, and myocardial blood flow and metabolism. With respect to fluorine NMR imaging, some investigations into such applications have been made. Suggestions have been presented involving the study of vascular system disorders, in conjunction with fluorocarbon blood substitutes, Holland, G. N. et al: .sup.19 F. Magnetic Resonance Imaging. J. Magnetic Resonance. 28:133-136 (1977), and the localization/kinetics of fluorocarbon following liquid breathing. Further, in vitro canine studies involving the investigation of the feasibility of fluorine as an agent for NMR imaging of myocardial infarction have also been performed. Thomas, S. R. et al: Nuclear Magnetic Resonance Imaging Techniques has developed Modestly Within a University Medical Center Environment: What Can the Small System Contribute at this Point? Magnetic Resonance Imaging. 1(1):11-21 (1981). Further, an NMR technique in an object other than an animal has been described for the determination of magnetic susceptibilities of oxygen in benzene or hexafluorobenzene solutions in order to estimate the amount of dissolved oxygen therein. For example, this method might be used for a remote control of oxygen content in organic solvents for oxygen pressures higher than one atmosphere. Delpuech, J. J., Hanza, M. A., and Serratrice, G.: Determination of Oxygen By a Nuclear Magnetic Resonance Method. J. Magnetic Resonance. 36:173-179 (1979). Finally, it has been demonstrated with NMR techniques in an object other than an animal that the solubilities of oxygen (in mole fractions) are higher in fluoroalkanes than in previously reported hexafluorobenzene. Hanza, M. A. et al: Fluorocarbons as Oxygen Carriers. II. An NMR Study of Partially or Totally Fluorinated Alkanes and Alkenes. J. Magnetic Resonance. 42:227-241 (1981).
As to biological gases, it is well known that in vivo gases are indicators with respect to diagnosing and monitoring physiological conditions in a host. Thus, it is critical to measure the gases with an accurate, inexpensive and reliable procedure. Heretofore, the biological gases measured in a host are practically limited to blood gases, and in particular, oxygen and carbon dioxide. Basically, the presently utilized procedures to measure blood gases include electrochemical, non-electrochemical, transcutaneous and infrared procedures. The electrochemical procedure is an analytical method designed to measure blood gases very accurately, inexpensively and quickly. In contrast, the non-electrochemical procedure, or the Van Slyke procedure is very slow, expensive and cumbersome. Unfortunately, both blood procedures are invasive requiring venipuncture or vascular intrusion. With respect to the transcutaneous procedure, this method is a continuous process capable of monitoring blood gases in a host over a period of time. The procedure requires the use of a Clark oxygen electrode probe to measure the blood gases. Finally, the infrared method, or the Jobsis procedure, measures the percent saturation of oxygen in the blood. However, this procedure requires subjecting the host to infrared rays.
It is apparent from the above brief overview directed to the limitation of NMR techniques and various methods for measuring in vivo gases and the current state of knowledge, that there is a need to provide improved methods that more effectively, measure, identify and monitor gases in an animal.